The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut

Abstract

Human inflammatory bowel disease (IBD), including Crohn disease and ulcerative colitis, is a chronic, relapsing, and remitting condition of unknown origin that exhibits various features of immunological inflammation and affects at least 1 in 1,000 people in Western countries (1-3).IBD is characterized by inflammation in the large and/or small intestine associated with diarrhea, hemoccult, abdominal pain, weight loss, anemia, and leukocytosis (1, 2).Studies in humans have implicated impaired mucosal barrier function, pronounced innate immunity, production of proinflammatory and immunoregulatory cytokines, and the activation of CD4 + T cells in the pathogenesis of IBD (1, 2).One of the major risk factors triggering and worsening the disease is the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) (4-6).Because NSAIDs share inhibition of the enzyme cyclooxygenase (COX) as a common mechanism, it is believed that the COX inhibition has adverse effects on IBD.Consistently, genetic disruption of either of the two isoforms of COX, COX-1, or COX-2, in mice exacerbated the extent of colitis in an experimental model ( 7).COX catalyzes production of prostanoids including prostaglandin D 2 (PGD 2 ), PGE 2 , PGF 2 , PGI 2 , and thromboxane (TX), which act on the respective receptors, the PGD receptor (DP), the PGE receptor (EP), the PGF receptor (FP), the PGI receptor (IP), and the TX receptor (TP) to exert their actions (8,9).EP has four subtypes, EP1, EP2, EP3, and EP4, which are encoded by different genes.The adverse effect of NSAIDs on IBD, therefore, indicates that during the course of IBD some prostanoids are formed and negatively modulate the extension of the disease.Indeed, in human IBD, a dramatic increase in prostanoid synthesis is found in the intestine and correlates with the disease activity (10-12).However, little is known about how prostanoids modulate IBD and which prostanoid and receptor are responsible for such modulation.Here we have used dextran sodium sulfate-induced (DSS-induced) colitis as a model of IBD (13) and subjected mice deficient in each type or subtype of prostanoid receptor individually to this treatment.DSS causes acute colitis by damaging epithelial cells and, thereby, stimulating regional inflammation through production of cytokines and other inflammatory mediators (13).The aim of this study is to